Glaucoma is a collection of ocular disorders that preferentially targets retinal ganglion cells for injury and eventually causes blindness if left untreated. A common feature of the disease is an increase in IOP caused by a reduction in outflow of aqueous fluid through the trabecular meshwork of the eye. The pressure increase can happen rapidly in the case of angle-closure glaucoma due to the iris coming in sudden contact with the meshwork, or it can proceed slowly in the case of open-angle glaucoma due a gradual decline in the outflow capacity of the eye.
The open-angle form is most prevalent and insidious because the symptoms are subtle and easily overlooked. By the time a clinical diagnosis is typically made, around half the population of retinal ganglion cells has already died [1]. This is tragic since the progression of the disease can be slowed with medicines that lower IOP. Part of the reason for the late diagnosis is not just the lack of awareness of a problem but also that ocular hypertension is not an obligatory feature of the disease. Some people with high IOP never show any signs of retinal injury, while others with normal IOP have pronounced visual deficits [3, 4]. Additional evidence is therefore needed from gonioscopy exams, optic disc inspections, and vision tests before the risks and costs of surgical or pharmacological intervention are acceptable and treatment is initiated.
Since retinal ganglion cells are irreplaceable at present time, there is a great need for a detailed understanding of what happens to the cells before they die so that the onset of the disease can he detected and treatment commenced at the earliest possible date. Such an understanding is difficult to obtain clinically because the structural and functional state of individual ganglion cells can only be accessed using invasive techniques. Researchers thereby rely heavily on animal models in which IOP is chronically increased by genetic or experimental means in order to learn about the mechanisms by which glaucoma inflicts damage upon the retina.
Genetic models of glaucoma are presently restricted to select strains of mice, the most studied of which is the DBA/2J inbred line. These mice have a mutation which causes iris pigment to slough off and accumulate in the trabeculum at around 6-8 months of age [5]. Since the ciliary body continues to produce aqueous fluid, the ensuing buildup of pressure in the eye leads to impaired retrograde transport, retrograde axonal degeneration, and then ganglion cell body apoptosis much like in humans [5, 6]. Genetic models have the advantages that the IOP increase is spontaneous, gradual like open-angle glaucoma, and automatic for every animal, which makes it possible to apply modern molecular tools to identify the critical genes and biochemical pathways involved in ganglion cell death [6, 7].
Disadvantages are that i) the mutations behind the model (since animals do not normally get glaucoma) has multiple cellular effects not all of which are known or ascribable to pressure, the mutational effects are generally bilateral so there is no internal control group for statistical comparisons, iii) the time of onset is uncertain without frequent IOP measurement, and iv) the small size of mice can be inconvenient for pressure monitoring and physiological testing.
Experimental models of glaucoma include a diversity of species and induction techniques. The first model to achieve widespread success was created in primate [8, 9], and later replicated in other mammals [10, 11], by photocoagulating the trabecular meshwork with an intense laser. Subsequently, rat models were introduced which target outflow pathways downstream of the meshwork for occlusion [12, 13]. One method is to cauterize episcleral veins on the eye surface, but the method has lost favor because the IOP elevation often dissipates after a few weeks [14] and the pattern of retinal damage differs noticeably from that in humans [2]. The more popular and established method is to inject a bolus of hypertonic saline into an episcleral vein [12, 15].
The saline scleroses timbal vasculature of the eye, causing IOP to rise over a couple weeks to a roughly sustained level that can last for months. These methods and variants of them have since been applied to mice and pigs [6, 16-19], and others are currently being explored such as intraocular injection of latex microspheres [20]. What is striking and exciting about these experimental models is that an injury inflicted solely to the front of the eye causes at the back of the eye an accumulation of organelles in the optic nerve head, a removal of optic disc capillaries and deposition of extracellular matrix proteins, and a preferential loss of large ganglion cells with non-ganglion cells left relatively untouched [1, 2, 21].
Experimental models have several advantages over genetic models for glaucoma research and some notable disadvantages. The main advantage is that only one eye experiences high IOP so the other eye can serve as a built-in control for hypothesis testing, which is especially important when the pressure exposure history is long because rodent eyes can undergo measurable age-related loss of ganglion cell number and function [22-24]. A second advantage is that the animal is physiologically normal in all respects except the treated eye. Optic nerve damage can therefore be causally linked to the treatment and in all likelihood to elevated IOP since it is the lone feature shared by the various experimental treatments. A third advantage is that ganglion cell activity can be recorded in rats and primates, but not as yet in mice, without disturbing or removing the eye or brain [25-27]. This allows for chronological studies of the changes in optic nerve information sent to the brain as the disease progresses. The main disadvantage is that IOP increases are not spontaneous so certain questions are impractical to address by experimental models in lieu of costs in time and effort.
While current methods of glaucoma induction in animal models are effective and widely employed, their usefulness for glaucoma research has important limitations [21]. For one, multiple experimental treatments are often necessary to suppress fluid outflow and raise IOP to a detrimental level, and even then some animals still do not develop ocular hypertension or the pressure increase is short-lasting. Multiple injections may result in as much as a month of time wasted checking whether the first injection was successful. Secondly, IOP must be frequently monitored to evaluate treatment success and chronicle the exposure history. This is impractical to do by hand with a tonometer, meaning that momentary variations in pressure over the course of a day go unrecorded. And thirdly, the temporal progression and amount of IOP change a given animal will experience is largely unpredictable.
Loosely similar pressure profiles can be expected, but the steady-state level might be higher or lower, might be reached more or less quickly, and might not go through peaks or midlevel plateaus. Such differences in pressure exposure could have an important bearing on disease pathology. A systematic, carefully controlled study of the effects of pressure history is currently impossible.
These limitations present a major impediment to continued progress in glaucoma research. As engineers know, in order to fully and correctly identify the properties of an unknown system from its outputs, the corresponding inputs to the system must be precisely specified and broadly distributed in strength and time. Yet, the state-of-the-art at the moment is to inject an agent into the eye and take occasional IOP readings in hopes that something happens.
Given these challenges, what is needed is a device and system that is capable of giving clinicians complete control of eye pressure as well as round-the-clock feedback on pressure for managing that control.